Neuropeptide Y (NPY) is a 36 amino acid-long polypeptide (NPY1-36; SEQ ID NO:22) widely distributed in the central and peripheral nervous system of mammals. NPY is the most abundant neuropeptide in the brain and is known to induce vasoconstriction, to inhibit noradrenaline release at a pre-synaptic level, and to regulate diverse functions including blood pressure, stress, pain, hormone secretion, reproduction, circadian rhythm and food intake. NPY has been implicated in feeding disorders, epilepsy, hypertension, pain disorders, depression and anxiety.
NPY is known to bind and stimulate receptors belonging to the GPCR family, also known as seven-transmembrane receptors (7TM); including Y1, Y2, Y3, Y4, Y5 and Y6 (aka y6). In the central nervous system, NPY predominantly acts via Y1, Y2 and Y5. These 7TM receptors display different affinities for full-length NPY and N-terminally truncated fragments thereof such as NPY3-36; a physiological cleavage product which loses affinity for the Y1 receptor to become an Y2/Y5 receptor agonist. NPY is known to exert neuroprotective and neurogenic effects reported to occur via activation of the GPCR NPY-receptors.
Nyce et al (U.S. Pat. No. 6,426,330) discloses NPY fragments of between 8 to 18 amino acids in length with a D-Thr amino acid substitution of the Thr32 position. A few specific peptide sequences are mentioned comprising the most C-terminal amino acid at position 36 of NPY, such as NPY27-36. The peptides are used for inducing satiety and lowering blood pressure.
During et al. (US2010/0168215) discloses expression vectors comprising a nucleic acid encoding NPY or a functional fragment thereof. The vector is for treating a neurological disease. The functional fragment of NPY is defined as retaining activity of full length NPY, namely being capable of binding to cognate NPY-receptors (especially Y2).
Specific fragments include NPY2-36, NPY13-36, NPY16-36 and NPY18-36, thus the disclosed fragments include the most C-terminal amino acid at position 36 of NPY.
Boublik et al (U.S. Pat. No. 5,026,685 and U.S. Pat. No. 5,328,899) discloses NPY analogues (NPY19-36 and NPY 17-36, respectively) shortened at the N-terminus, and their use i.a. for lowering blood pressure.
Abid et al. (J Biol Chem Vol 284, No 37, pp. 24715-24724, 2009) discloses that NPY1-36 is rapidly cleaved in serum to produce three main fragments namely NPY3-36, NPY3-35 and NPY2-36. NPY3-35 is shown to be unable to bind NPY Y1, Y2 and Y5 receptors and thus it is concluded to represent the major metabolic clearance product of the Y2/Y5 agonist NPY3-36.
Current clinical trials involving NPY are largely focused on treating obesity although its more recently discovered neuroprotective and neurogenic effects make it a potential candidate for treating nervous system disorders including depression, Alzheimer's disease, Parkinson's disease and epilepsy. However, NPY-based treatments have a range of potential serious adverse effects because of the broad functions exerted by the various GPCR NPY-receptors targeted: As an example, targeting Y1 via NPY is likely to cause hypertension, anxiety, depression and altered pain perception.